1. Field of the Invention
The invention relates to non-thrombogenic articles and to methods of reducing thrombogenicity associated with polymer resin articles.
2. Brief Description of the Prior Art
Representative of the prior art are the disclosures of U.S. Pat. Nos. 3,457,098; 3,634,123; 3,810,781; 3,846,353; and 4,118,485. As succinctly stated in U.S. Pat. No. 3,846,353, "It has been known for many years that a basic problem in the development of prostheses for intravascular replacement lies with the complicated processes occurring at the blood-graft interface. The addition of a solid foreign material to the blood stream results in clot formation on that material. This interface activity occurs no matter what the foreign material might be. Porous prosthetics have proven to be useful in the larger vessel, but have failed when adapted to the smaller artery. Certain non-porous materials have been used but also have demonstrated various disadvantages. Solid or imperforate materials are preferred in the field of artificial internal organ development. Pumping chambers, arteries and materials for encompassing structures having moving parts would demand the property of elasticity as its constituent, prompting an additional requirement of the ideal vascular prosthetic material. It would also be advantageous if that same material could be varied in its elastic properties to the point of rigidity.
"Naturally, polymers, both natural and synthetic and particularly certain synthetic plastics have come to the fore as preferred materials for these prosthetics. Their major drawback, however, is their thrombogenicity. Even though plastics are used in various apparatus such as heart-lung machines, kidney machines, and artificial heart valves and patches, the tendency of these materials to cause coagulation necessitates the use of anticoagulants such as heparin. Even such plastics as Teflon (polytetrafluoroethylene) and the silicone rubbers which are more compatible with blood than most plastics, still show thrombogenic characteristics. The first real advance in the preparation of nonthrombogenic materials was described by Dr. Vincent Gott. The method used by Dr. Gott comprised treating a graphited surface first with Zephiran (benzalkonium chloride) and then with heparin. Materials treated in this way were nonthrombogenic in vivo for long periods of time. The major disadvantage, however, with these materials, was that the method could only be practiced on rigid plastics and a need still exists for a suitable flexible nonthrombogenic plastic, as well as a method of producing the same.
"Various methods have been devised for producing such a material, most of which involve chemically bonding a quaternary ammonium salt to the polymer and then heparinizing the same. Usually, this is done by incorporating an amine in the polymer, quaternizing the amine, and then heparinizing the quaternized material. The disadvantages associated with these methods are numerous. The materials prepared by these methods have usually been satisfactory on a small laboratory scale, but could not easily be scaled up to a practical method. Furthermore, these methods were quite satisfactory for preparation and evaluation of individual polymers, the techniques varying from polymer to polymer. A major drawback, based on these differences in techniques, is that heparinization of a composite structure containing more than one type of polymer could not be easily done. Moreover, many of the techniques involve several steps requiring a variety of reagents, solvents, and reaction conditions."
Many of the disadvantages and drawbacks of the earlier methods for rendering polymeric materials less thrombogenic were removed in the methods described in the above-identified U.S. patent applications. These latter methods comprise:
first absorbing on the surface of the material, a quaternary ammonium salt. The material is then "heparinized" by exposure to a salt of heparin in solution. The heparin is bound to the polymer material through ionic bonds with the surface absorbed quaternary ammonium salt. The treated polymeric materials exhibit an advantageous reduction in thrombogenicity as reflected by extended periods of time during which the materials may be in contact with blood without inducing thrombosis. In addition, it has been observed that the quaternary ammonium salt-heparin complex treated materials of the prior art have a degree of toxicity toward the blood or the host animal in which the treated polymer is implanted. It is believed that the toxicity is generated by leaching of the quaternary compound from the polymer substrate over a period of time.
By the method of our invention, relatively stable articles for use in association with whole blood are obtained, which exhibit unexpectedly low toxicity and unexpectedly reduced thrombogenecity as reflected by unusually long periods of time during which they may be in contact with blood without inducing a thrombosis. By the method of the invention, preformed articles, i.e.; valves, pins, containers, tubing and the like, may be treated to reduce thrombogenicity without increasing toxicity and without altering the geometry, configuration and/or dimensions of the article. This also obviates the need for post-forming the article as often necessitated in prior art treatments by shrinking or swelling or deterioration of the treated article.